Long-term effects of Helicobacter pylori eradication in Mongolian gerbils

Background: In this study, to clarify whether Helicobacter pylori eradication alters the course of the development of gastric mucosal changes in the stomach, we examined the long-term effects of H. pylori eradication on H. pylori-inoculated gerbils. Methods: A total of 40 H. pylori-inoculated gerbils were randomized and subjected, at 22 months after inoculation, to eradication treatment with dual therapy of omeprazole plus clarithromycin, or with therapy with a novel quinolone compound, Y-34867, alone. The animals were killed at the start of administration (control group) or at 8 months after the completion of therapy (vehicle or eradication-treatment groups). Results: Severe histopathological changes in the gastric mucosa were observed in all H. pylori-inoculated gerbils at the start of administration. At 8 months after completion of therapy, the frequency of gastritis, erosion, intestinal metaplasia, and gastric carcinoid in the eradication therapy groups was markedly reduced compared with that in the control and vehicle groups. Values for anti-H. pylori IgG titer, bacterial counts, and gastrin also decreased significantly. Conclusions: These results suggest that H. pylori eradication may have had a therapeutic effect not only on gastritis, erosion, and gastric ulcer but also on glandular atrophy, intestinal metaplasia, and gastric carcinoid. Received: November 8, 2001 / Accepted: May 31, 2002 Reprint requests to: F. Hirayama     

Five‐year follow‐up study on histological and endoscopic alterations in the gastric mucosa after Helicobacter pylori eradication

Background: To investigate long‐term changes in the gastric mucosa after Helicobacter pylori eradication, we examined histological and endoscopic ?ndings of the gastric mucosa before and 5 years after eradication. Methods: The subjects comprised 59 H. pylori‐positive patients with peptic ulcer who had been periodically followed for 5 years after H. pylori eradication. Acid‐suppressive drugs were not given after eradication, and endoscopic examination and tests for H. pylori infection (urea breath test (UBT), culture and histology) were performed before and 1 to 2 months, 1 year, and 5 years after eradication. Biopsy samples were taken from the greater curvature of the gastric antrum and upper corpus, and were scored histologically according to the Updated Sydney System. The atrophic border was evaluated endoscopically based on Kimura and Takemoto's classi?cation. Antral erosion and spotty redness in the corpus were also scored. Results: (1) Neutrophil in?ltration was signi?cantly reduced 1 to 2 months after eradication and remained around the reduced level over the next 5 years. Mononuclear cell in?ltration began to decrease 1 to 2 months after eradication and continued to subside 1 year and 5 years later. (2) Histological atrophy of the gastric glands was signi?cantly improved 1 year and 5 years after eradication. However, endoscopy revealed no consistent alteration in the atrophic border. (3) There was no signi?cant change in the degree of intestinal metaplasia for 5 years. (4) In some cases, antral erosion became more conspicuous after 5 years. Spotty redness in the corpus was observed in 15% of cases (9/59) before and 10% (6/59) 1 year after eradication, but had disappeared in all cases 5 years later. Conclusions: Neutrophil in?ltration improved rapidly after H. pylori eradication in contrast with mononuclear cell in?ltration, which decreased gradually over 5 years. Glandular atrophy improved in the long term, whereas intestinal metaplasia had not altered 5 years after eradication. Spotty redness in the gastric corpus disappeared in all cases after eradication, suggesting that it is an endoscopic ?nding related to H. pylori infection.     

Correlation between serum pepsinogen levels and gastric mucosal histological findings before and after Helicobacter pylori eradication therapy

Background: Helicobacter pylori causes chronic gastritis and is also associated with many other gastrointestinal diseases. The incidence of gastric cancer is thought to vary according to the degree and topography of chronic gastritis. Histological findings of specimens obtained at endoscopy are therefore important. In the present study, we investigated the correlation between these histological findings and serum pepsinogen (PG) levels. Methods: Helicobacter pylori eradication therapy was conducted in 100 H. pylori‐positive patients. Endoscopies were performed prior to, and 2 months after, eradication therapy; gastric mucosal biopsies were taken from the antrum and corpus. Helicobacter pylori infection was diagnosed using the rapid urease test, culture and histology. Using the Updated Sydney System, histological findings of inflammation, activity, atrophy and intestinal metaplasia were each graded. Blood was taken on the same two occasions for determination of serum levels of PG I and II. Results: Levels of PG I were highest in association with antrum‐predominant gastritis (APG), followed in order by pangastritis (PAN) and corpus‐predominant gastritis (CPG), with a significant difference between APG and CPG. No correlations were seen between PG II levels and gastritis topography. Examination of the relationship between PG levels and histological findings revealed significant correlations between PG I levels after eradication atrophy and intestinal metaplasia in the gastric corpus. No significant correlations were seen between PG II levels and before or after eradication histological findings. Conclusion: Our results indicate that serum PG levels may be a useful indicator of before‐eradication gastritis topography and after‐eradication gastric atrophy in the gastric corpus.     

Analysis of factors associated with recovery of the serum pepsinogen ratio after Helicobacter pylori eradication: a long-term follow-up study in Korea

Abstract

Objective: Serum levels of pepsinogen (PG) are related to Helicobacter pylori-induced inflammation of the gastric mucosa. This study aimed to examine the influence of H. pylori eradication on serum PG, analyze its associated factors, and evaluate the long-term outcomes.

Methods: H. pylori-positive patients who underwent gastroscopy and serum PG measurement were enrolled in a single academic hospital. After H. pylori eradication, the measurement of serum PG level was performed. Recovery of serum PG I/II ratio was defined as a PG I/II ratio after eradication of >3.0 in patients with a PG I/II ratio ≤ 3.0 before eradication. Follow-up involved serum PG measurement and gastroscopy with a rapid urease test annually.

Results: In all, 327 patients were eligible for study inclusion. Compared to those before H. pylori eradication, serum PG I (74.9 vs. 44.3?ng/mL, p?<?.001) and PG II (25.4 vs. 9.1?ng/mL, p?<?.001) levels significantly decreased after successful eradication. In addition, there was a significant increase in serum PG I/II ratio after eradication (3.07 vs. 4.98, p?<?.001). In multivariate analyses, the following were independently associated with failed recovery of serum PG I/II ratio despite successful eradication: age ≥ 60?years (odds ratio [OR]?=?0.231, 95% confidence interval [CI]?=?0.084–0.629, p?=?.004) and severe gastric atrophy (OR = 0.156, 95% CI = 0.055–0.440, p?<?.001).

Conclusions: Recovery of serum PG I/II ratio after H. pylori eradication may be achieved in H. pylori-infected patients aged <60?years without severe gastric atrophy.     

Amount of Helicobacter pylori in gastric mucus during anti-H. pylori treatment

Helicobacter pylori is present in infected patients not only on the gastric epithelial cell surface but also in gastric mucus. We developed a competitive polymerase chain reaction (cPCR) method for quantitative measurement of H. pylori in gastric mucus. The aim of this study was to determine the number of H. pylori in gastric mucus before and after anti- H. pylori treatment. Patients with duodenal ulcer were treated with lansoprazole alone ( n =11) or lansoprazole and amoxycillin ( n =12). The amount of H, pylori in gastric mucus was measured over time by a cPCR assay. Helicobacter pylori infection was also tested for using histology, culture, and the rapid urease test (RUT). Although most patients treated with lansoprazole alone had become H. pylori -negative by the end of treatment when tested by histology, RUT, and culture, a large number of H. pylori organisms were found in the gastric mucus at that time by cPCR. These patients returned to being H. pylori positive 1 to 12 months later on the basis of histology, RUT, and culture. However, cPCR results indicated eradication of H. pylori by the end of treatment in eight of the 12 patients treated with lansoprazole and amoxicillin, and these patients remained H. pylori negative on histology, RUT, culture, and cPCR 1 to 12 months later. Testing for H. pylori in gastric mucus is thus useful for precise determination of the success or failure of H. pylori eradication therapy.     

Histological changes of gastric mucosa after Helicobacter pylori eradication:a systematic review and meta-analysis

AIM:To systematically review pathological changes of gastric mucosa in gastric atrophy(GA)and intestinal metaplasia(IM)after Helicobacter pylori(H.pylori)eradication.METHODS:A systematic search was made of PubMed,Web of Science,EMBASE,ClinicalTrials.gov,OVID and the Cochran Library databases for articles published before March 2013 pertaining to H.pylori and gastric premalignant lesions.Relevant outcomes from articles included in the meta-analysis were combined using Review Manager 5.2 software.A Begg’s test was applied to test for publication bias using STATA 11software.χ2 and I2 analyses were used to assess heterogeneity.Analysis of data with no heterogeneity(P>0.1,I2<25%)was carried out with a fixed effects model,otherwise the causes of heterogeneity were first analyzed and then a random effects model was applied.RESULTS:The results of the meta-analysis showed that the pooled weighted mean difference(WMD)with 95%CI was 0.23(0.18-0.29)between eradication and non-eradication of H.pylori infection in antral IM with a significant overall effect(Z=8.19;P<0.00001)and no significant heterogeneity(χ2=27.54,I2=16%).The pooled WMD with 95%CI was-0.01(-0.04-0.02)for IM in the corpus with no overall effect(Z=0.66)or heterogeneity(χ2=14.87,I2=0%)(fixed effects model).In antral GA,the pooled WMD with 95%CI was 0.25(0.15-0.35)with a significant overall effect(Z=4.78;P<0.00001)and significant heterogeneity(χ2=86.12,I2=71%;P<0.00001).The pooled WMD with 95%CI for GA of the corpus was 0.14(0.04-0.24)with a significant overall effect(Z=2.67;P=0.008)and significant heterogeneity(χ2=44.79,I2=62%;P=0.0003)(random effects model).CONCLUSION:H.pylori eradication strongly correlates with improvement in IM in the antrum and GA in the corpus and antrum of the stomach.     

Histological characteristics of gastric mucosa prior to Helicobacter pylori eradication may predict gastric cancer

Abstract

Objective. Although Helicobacter pylori (H. pylori) eradication has been shown to inhibit gastric cancer, it does not completely suppress it. Therefore, risk factors of gastric cancer development following H. pylori eradication were examined. Material and methods. A total of 2355 patients (1501 males and 824 females) underwent successful eradication of H. pylori. Endoscopic atrophy, histological gastritis, atrophy, intestinal metaplasia (IM), and operative link for gastritis assessment (OLGA) staging were subsequently evaluated. Results. Following eradication, 33/2355 patients (25 males and 8 females) developed gastric cancer. Compared to a nongastric cancer group that was matched according to gender and age, the incidence of endoscopic atrophy (3.52 ± 1.45 vs. 4.85 ± 1.18, p < 0.001), histological atrophy at the greater curvature of the antrum (1.42 ± 0.80 vs. 1.95 ± 0.86, p = 0.0059), inflammation (2.05 ± 0.59 vs. 2.33 ± 0.66, p = 0.031), IM at the greater curvature of the corpus (0.06 ± 0.30 vs. 0.24 ± 0.54, p = 0.029), the ratio of OLGA-stage 0–II/III, IV (13/8 vs. 55/11, p = 0.038) were significantly higher for the gastric cancer group. Multivariate analysis also showed the highest odds ratio (6.26, 95% confidence interval or CI, 1.28–30.60, p = 0.023) for IM at the greater curvature of the corpus. Conclusions. Severe endoscopical atrophy, OLGA staging, histological atrophy at the antrum, inflammation, and particularly IM at the corpus, were identified as risk factors for gastric cancer development following H. pylori eradication. Therefore, eradication should be performed before these predictors develop.     

Does Helicobacter pylori infection affect gastric emptying in patients with functional dyspepsia?

The objectives of the study were first, to determine if gastric emptying was altered in patients with functional dyspepsia with and without Helicobacter pylori infection compared with normal healthy volunteers; and second, to determine if there were further alterations in gastric emptying when the infection was eradicated. Gastric emptying was measured using a ^99mtechnetium radiolabelled solid meal and gastric emptying time was measured as t_1/2, viz. time taken for half the radiolabelled meal to be emptied from the stomach. The mean gastric emptying time for H. pylori-positive patients (n= 20) was 56.4±24.8 min; H. pylori-negative patients (n= 19) 67.8±31.8 min; and normal controls (n= 20) 58.8 ± 18.8 min. No significant difference was obtained between the groups (ANOVA; P= 0.348). Thirteen of 18 H. pylori-positive patients successfully eradicated the infection following treatment with omeprazole 40 mg o.m. and amoxycillin 500 mg t.d.s. for 2 weeks. The mean difference in the gastric emptying time before and H. pylori eradication was 23.9 + 13.2 min (P= 0.556). There was no significant difference in the frequency of specific dyspeptic symptoms as well as the overall mean symptom score between the H. pylori-positive and -negative patients. Gastric emptying was not different between patients with functional dyspepsia and normal controls. Helicobacter pylori infection does not appear to affect gastric emptying in patients with functional dyspepsia.     

Cap polyposis cured by Helicobacter pylori eradication therapy

Helicobacter pylori eradication. A 63-year-old man was diagnosed as having cap polyposis with mucoid stool, diarrhea, and bleeding on defecation. Following 5 weeks of total parenteral nutrition, his symptoms and hypoproteinemia improved and he was discharged, although follow-up colonoscopic findings revealed no improvement. Subsequent gastroscopy revealed diffusely erosive polyps with cap-like “fur” from the angle to the antrum of the stomach, similar to the lesions observed in the colon. Because H. pylori infection was demonstrated in the stomach, eradication therapy was administered. After this treatment, his symptoms immediately disappeared, and the polypoid lesions in the colon and stomach had completely disappeared 8 months later. Because there have been no previous reports of a relationship between H. pylori and cap polyposis, this case is of great interest. Received: June 18, 2001 / Accepted: November 30, 2001     

A short-term eradication therapy for Helicobacter pylori acute gastritis

BACKGROUND AND AIMS: Acute gastritis, caused by an initial infection of Helicobacter pylori (H. pylori), may resolve spontaneously, but the infection sometimes becomes chronic. We examined the efficacy of a short-term H. pylori eradication therapy on acute gastritis. METHODS: Among the 15 patients with hemorrhagic acute gastritis who were randomly allocated to group A (eradication therapy) or group B (Lansoprazole, LPZ), 10 of them started to receive treatment within 1 day after the disease onset. The other five patients began the eradication therapy 4-6 days after disease onset (group C). Eradication therapy consisted of a daily oral administration of each of 30 mg lansoprazole (LPZ), once a day; 400 mg clarithromycin, twice a day; 1000 mg amoxicillin, twice a day; and 300 mg rebamipide, three times a day, for one week. If the endoscopy was normal, medication was stopped for the following 4 weeks before gastric endoscopy was performed again in order to assess H. pylori eradication. RESULTS: All group A patients were cured after the 1-week treatment and therefore, they became H. pylori negative. Group B and C patients had erosions or ulcers after the 1-week treatment and so received an additional 3-week administration of LPZ. Four weeks later, their gastritis was cured and except for one group B patient, they became H. pylori-negative. CONCLUSION: In patients with acute gastritis, caused by an initial H. pylori infection, eradication therapy was efficacious in achieving early healing. This therapy should be started as soon as possible after disease onset.     

Endoscopic duodenitis, gastric metaplasia and Helicobacter pylori

BACKGROUND AND AIMS: The purpose of this study was to investigate the relationship between gastric metaplasia and Helicobacter pylori in patients with endoscopic duodenitis. METHODS: The subjects were 57 patients with endoscopic duodentitis with or without H. pylori-associated gastritis. Biopsy specimens were obtained from the stomach and duodenal bulb to assess the histological findings and H. pylori infection. Gastric metaplasia was divided into three types: complete, intermediate and incomplete, according to the amount of mucus in the metaplastic cells. In 10 H. pylori-positive patients, endoscopic and histological findings of duodenitis were compared before and after eradication of the bacteria. RESULTS: There was no significant difference in the extent of gastric metaplasia or the appearance and severity of endoscopic duodenitis between H. pylori-positive and -negative groups. The complete type of gastric metaplasia was frequently detected in the H. pylori-negative group, whereas the incomplete type was frequently observed in the H. pylori-positive group. After eradication of H. pylori, the incomplete type changed to the complete type with a decrease of histological inflammation. CONCLUSIONS: The complete type of gastric metaplasia occurred frequently without H. pylori infection, whereas the incomplete type was frequently associated with H. pylori infection.     

共同治疗策略对根除幽门螺杆菌的影响

[目的]研究存在幽门螺杆菌(Hp)感染家庭聚集的感染患者Hp根除治疗后复发情况,探讨共同根除治疗策略对远期根除Hp的影响。[方法]通过对内镜检查确诊的195例Hp感染患者的家庭成员采用13碳呼气试验进行Hp感染调查,筛选有家庭成员Hp感染的患者140例。按照对Hp感染家庭成员有无根除治疗,将140例随机分成家庭成员共同根治组和单独根治组,每组70例。治疗后每月随访患者感染复发情况,观察不同根治策略对Hp根除的影响。[结果]134例患者参与根治后4、6、12、18、24个月随访,其中家庭成员共同根除治疗患者68例,Hp感染复发患者分别为0、1、2、4、5例,累积复发率为7.4%,平均复发时间为(12.6±6.1)个月;而66例单独根治患者复发者则分别为3、5、9、11、13例,累积复发率为19.7%,平均复发时间为(11.1±6.3)个月。χ2检验分析发现,在根除治疗后4、6个月时,2组复发率比较差异无统计学意义(P0.05);随着时间推移,治疗后12、18、24个月,共同根治组患者Hp感染再发率显著少于单独根治组(P0.05)。[结论]从远期观察,对于存在Hp感染家庭聚集的Hp感染患者,Hp感染成员共同根除治疗可有效降低根治后感染再发。     

Factors influencing Helicobacter pylori eradication with 2 week combination therapy of lansoprazole and amoxycillin: Intragastric distribution of colonization and gastric mucosal atrophy

In Japan, gastric ulcers are often accompanied by marked gastric mucosal atrophy. We evaluated the dual therapy of double-dose lansoprazole and amoxycillin for Helicobacter pylori eradication in Japanese ulcer patients and investigated the effects of intragastric distribution of H. pylori colonization and gastric mucosal atrophy on eradication with this combination therapy. Seventy-six H. pylori-positive ulcer patients received lansoprazole (30 mg) plus amoxycillin (500 mg) twice daily for 2 weeks (LA-60 group), lansoprazole (30 mg once daily) plus amoxycillin (500 mg twice daily) for 2 weeks (LA-30 group) or lansoprazole (30 mg once daily) for 6 or 8 weeks (LPZ group). Infection was evaluated by light microscopy, culture and biopsy urease tests. Helicobacter pylori colonization was classified as localized to the corpus (localized type) or involving the antrum and corpus (whole type). Fundic mucosal atrophy was graded according to endoscopic and histological features. Eradication was achieved in 67.6% in the LA-60 group, 31.6% in the LA-30 group, and 0% in the LPZ group, and moderate or severe histological gastritis was improved in the LA-60 group. Eradication was better in localized-type colonization (92%) than whole-type (56%), and better with fundic mucosal atrophy (84%) than without, but poor in both whole-type colonization and scanty mucosal atrophy (47%). The LA-60 therapy achieves better eradication in Japanese ulcer patients with localized H. pylori colonization and/or gastric mucosal atrophy, which are likely to be important predictors for the successful eradication with dual therapy.     

Endoscopically demonstrable esophageal changes after Helicobacter pylori eradication in patients with gastric disease

BACKGROUND AND AIMS: An increased prevalence of reflux esophagitis has been reported following Helicobacter pylori (H. pylori) eradication in patients with duodenal ulcers in Western countries. However, it has remained unknown whether this might also appertain to individuals with other diseases. We therefore carried out this study to determine the effect of eradicating H. pylori infection in a series of Japanese patients. METHODS: Of a total of 203 H. pylori-positive patients successfully cured of infection, 82 cases (58 males, 24 females) with gastric disease, but not duodenal ulcers, were included in the present study; median age 56 years (range 18-80) and median follow up of 24 months (range 6-65). The patients were investigated clinically and endoscopically at regular intervals. RESULTS: Mild reflux esophagitis developed after eradication in three of 55 (5.5%) patients formerly without this condition, while it improved after eradication in five of 27 (18.5%) patients, with the disease endoscopically diagnosed prior to eradication. The estimated incidence of esophagitis within 3 years was 4.8% after cure of infection. Short segment Barrett's esophagus developed after eradication in six of 58 (10.3%) patients who did not have it prior to the therapy, while the condition did not improve in 24 patients affected before eradication. CONCLUSIONS: Endoscopic esophageal changes after H. pylori eradication in the present series of Japanese patients were relatively infrequent and mild. This therapeutic approach thus appears to be safe and unproblematic.     

Helicobacter pylori reinfection rate 3 years after successful eradication

BACKGROUND AND AIM: Helicobacter pylori (HP) infection is one of the most prevalent human infections and has been implicated as a predisposing factor in gastric cancer, chronic active gastritis, duodenal ulcer, gastric ulcer and gastric lymphoma. Reinfection after successful eradication is quite uncommon in adults. In the only study carried out in Iran, a reinfection rate of 19.1% after 1 year has been reported. We studied the rate of reinfection 3 years after successful HP eradication. METHODS: All patients who had undergone HP eradication 3 years before the study and had successful eradication verified by a negative (14)C urea breath test (UBT) 1 year after eradication were invited to complete a questionnaire and undergo another UBT. In addition, spouses and the offspring of those testing positive were offered an UBT. RESULTS: Ninety-eight patients were enrolled (49% male). Mean age was 44 +/- 13 years (range: 18-75 years). Twenty patients (20.4%) had a positive UBT. Epigastric burning (25%vs 69%) and pyrosis (50%vs 67%) were seen less commonly in those who were HP free at 3 years compared to those who tested positive for HP. CONCLUSIONS: According to our data, in our region the HP reinfection rate is 20.4% 3 years after successful eradication.     

Helicobacter pylori infection and the risk of gastric cancer among the Korean population

Helicobacter pylori infection has been associated with chronic atrophic gastritis, a precursor of gastric cancer. We conducted a prospective, case-controlled study to investigate whether H. pylori infection increases the risk of gastric cancer in Korean people with a high risk of gastric cancer. We enrolled 160 gastric cancer patients who were confirmed by endoscopic biopsy during 1994 and 160 age-matched control subjects with non-ulcer dyspepsia were compared to document the relationship between H. pylori infection and gastric cancer. The presence of H. pylori infection was determined by the rapid urease test and/or histology by Wright-Giemsa staining. The overall presence of H. pylori infection was 60% in gastric cancer patients and 51.9% in age-matched control subjects (odds ratio 1.39; 95% confidence interval 0.894–2.17; P= 0.143). Carcinomas of cardia, body and antrum were not associated with H. pylori infection (odds ratio 1.43, 1.69 and 1.29, respectively; 95% confidence interval, 0.271–7.52, 0.787–3.62 and 0.689–2.43, respectively; P= 0.178, 0.177 and 0.642, respectively) nor was the intestinal or diffuse type of cancer (odds ratio 1.39 and 1.40, respectively; 95% confidence interval 0.791–2.45 and 0.681–2.87, respectively; P= 0.250 and 0.835, respectively). Gender was not a risk for gastric cancer. In contrast to previous studies, these results do not provide evidence of H. pylori infection for gastric carcinogenesis in Korea.     

Enhanced somatostatin secretion into the gastric juice with recovery of basal acid output after Helicobacter pylori eradication in gastric ulcers

BACKGROUND AND AIM: Antral somatostatin interacts with gastric acid secretion. We aimed to investigate the effect of eradication on gastric acid, somatostatin secretion and mucosal histology in gastric ulcer patients with Helicobacter pylori (H. pylori) infection. METHODS: Twenty-eight patients (21 male, 7 female) with H. pylori-positive gastric ulcer were treated with dual therapy. Before and 4-8 weeks after the therapy, the histology of biopsy specimens, basal acid output (BAO) and maximal acid output (MAO) after stimulation with tetragastrin were assessed. Somatostatin concentration in the gastric juice was measured by radioimmunoassay, and somatostatin output during either the basal or gastrin-stimulated period was also examined. RESULTS: Eradication was successful in 22 patients. Before treatment, the acid and somatostatin output were inversely related to the severity of neutrophil infiltration in the corpus and antrum, respectively. After successful eradication, improvement of histological inflammation and an increase in BAO, basal and gastrin-stimulated somatostatin output were observed. Eradication had no effect on atrophy and MAO. There was a positive correlation between gastric acid and somatostatin output in the basal or stimulated condition, irrespective of H. pylori infection. CONCLUSIONS: The present results suggest that recovery of gastric BAO may be caused by an improvement in corpus neutrophil infiltration, but not by an increase in parietal cell volume or a change in atrophy. Also, there was an increase in basal and gastrin-stimulated somatostatin-containing cell activity accompanied by improved antral neutrophil infiltration in the early phase after H. pylori eradication in gastric ulcers.